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Photocatalytic Dearomative Intermolecular [2 + 2] Cycloaddition of Heterocycles for Building Molecular Complexity
Abstract
Indole and indoline rings are important pharmacophoric scaffolds found in marketed drugs, agrochemicals, and biologically active molecules. The [2 + 2] cycloaddition reaction is a versatile strategy for constructing architecturally interesting, sp3-rich cyclobutane-fused scaffolds with potential applications in drug discovery programs. A general platform for visible-light mediated intermolecular [2 + 2] cycloaddition of indoles with alkenes has been realized. A substrate-based screening approach led to the discovery of tert-butyloxycarbonyl (Boc)-protected indole-2-carboxyesters as suitable motifs for the intermolecular [2 + 2] cycloaddition reaction. Significantly, the reaction proceeds in good yield with a wide variety of both activated and unactivated alkenes, including those containing free amines and alcohols, and the transformation exhibits excellent regio- and diastereoselectivity. Moreover, the scope of the indole substrate is very broad, extending to previously unexplored azaindole heterocycles that collectively afford fused cyclobutane containing scaffolds that offer unique properties with functional handles and vectors suitable for further derivatization. DFT computational studies provide insights into the mechanism of this [2 + 2] cycloaddition, which is initiated by a triplet-triplet energy transfer process. The photocatalytic reaction was successfully performed on a 100 g scale to provide the dihydroindole analog.
... The exergonic cycloadditions of 1,3-dienes with alkenes, capable of generating various ring systems, are amongst the most fundamental transformations in synthetic chemistry 17,18 . Recently, this classical realm has witnessed rapid advancements owing to the introduction of aromatics as reactants by the visible-light energy-transfer process [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] . Stemming from our reported [4 + 2]-dearomative cycloaddition between aza-arenes and alkenes 29 , we questioned whether the established reactivity could be diverted towards a cascade dearomative cycloaddition/rearrangement reaction forming unusual fused 2D/3D rings (Fig. 1c). ...
... As shown in Fig. 5, the quinoline scope of this [2 + 2] cycloaddition/cyclopropanation reaction was further evaluated. As a result, 6-chloroquinolines with additional substituents at any of the 2-, 3-or 4-positions exhibited excellent compatibility (26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36). The topology of the fused ring products was expanded by using tricyclic quinoline-derivative substrates (37)(38)(39). ...
Hybrid fused two-dimensional/three-dimensional (2D/3D) rings are important pharmacophores in drugs owing to their unique structural and physicochemical properties. Preparation of these strained ring systems often requires elaborate synthetic effort and exhibits low efficiency, thus representing a limiting factor in drug discovery. Here, we report two types of energy-transfer-mediated cascade dearomative [2 + 2] cycloaddition/rearrangement reactions of quinoline derivatives with alkenes, which provide a straightforward avenue to 2D/3D pyridine-fused 6−5−4−3- and 6−4−6-membered ring systems. Notably, this energy-transfer-mediated strategy features excellent diastereoselectivity that bypasses the general reactivity and selectivity issues of photochemical [2 + 2] cycloaddition of various other aromatics. Tuning the aza-arene substitutions enabled selective diversion of the iridium photocatalysed energy transfer manifold towards either cyclopropanation or cyclobutane-rearrangement products. Density functional theory calculations revealed a cascade energy transfer scenario to be operative. Hybrid 2D/3D ring systems have emerged as important scaffolds in medicinal chemistry, but efficient protocols for their synthesis are scarce. Now, energy-transfer-mediated cascade dearomative [2 + 2] cycloaddition/rearrangement reactions are developed to provide facile access to pyridine-fused 2D/3D ring systems.
... A major drawback of direct excitation is that most organic substrates require harsh, ionizing ultraviolet (UV) light irradiation, which often results in undesired and competitive side reactions. Therefore, the synthetic community has recently focused on the use of milder visible light to enable ENT processes to overcome these selectivity and activation issues [19][20][21][22] . ...
... Furthermore, a 2-quinolone derivative, a nitrogen analogue of coumarin, reacted in good yields to furnish the respective product 3ac. The potential of this strategy was further illustrated by use of different flavones (3ad-3af) and indoles (3ag-3al) as heterocyclic olefin coupling partners (Fig. 3a) 21,36 . Those products show a particularly high structural and functional group density as highlighted by product 3al bearing three contiguous fully substituted carbon centres. ...
For more than one century, photochemical [2+2]-cycloadditions have been used by synthetic chemists to make cyclobutanes, four-membered carbon-based rings. In this reaction, typically two olefin subunits (two π-electrons per olefin) cyclize to form two new C–C σ-bonds. Although the development of photochemical [2+2]-cycloadditions has made significant progress within the last century, research has been focused on such [2π+2π]-systems, where two π-bonds are converted into two new σ-bonds1,2. Here, we report an intermolecular [2+2]-photocycloaddition which uses bicyclo[1.1.0]butanes (BCBs) as 2σ-electron reactants3–7. This strain-release-driven [2π+2σ]-photocycloaddition reaction was realized by visible light-mediated triplet energy transfer catalysis8,9. A simple, modular, and diastereoselective synthesis of bicyclo[2.1.1]hexanes (BCHs) from heterocyclic olefin coupling partners, namely coumarins, flavones and indoles, is disclosed. Given the increasing importance of BCHs as bioisosteres – groups which convey similar biological properties to those they replace – in pharmaceutical research and considering their limited access10,11, there remains a need for new synthetic methodologies. Applying this strategy allowed us to extend the intermolecular [2+2]-photocycloadditions to σ-bonds and provides previously inaccessible structural motifs.
... To the best of our knowledge, the only known example on aza-[2 + 2] photocycloaddition (aza-Paternò-Büchi reactions) of indoles with imines were realized in an intramolecular setting 26 , despite the precedence of analogous reactions with ketone partners that forms oxetane-fused indolines 30,31 Intermolecular indole-imine aza-Paternò-Büchi reaction remain elusive. The major challenges arise from two aspects: [32][33][34][35] (1) Competitive formation of indole homodimers, head-to-head (H-H)/head-to-tail (H-T) or endo/exo heterodimers (Fig. 1b); (2) Low photoreactivity of imine chromophores and notorious E/Z isomerization, oxidation, hydrolysis at their excited state. ...
Small molecules with conformationally rigid, three-dimensional geometry are highly desirable in drug development, toward which a direct, simple-to-complexity synthetic logic is still of considerable challenges. Here, we report intermolecular aza-[2 + 2] photocycloaddition (the aza-Paternò–Büchi reaction) of indole that facilely assembles planar building blocks into ladder-shape azetidine-fused indoline pentacycles with contiguous quaternary carbons, divergent head-to-head/head-to-tail regioselectivity, and absolute exo stereoselectivity. These products exhibit marked three-dimensionality, many of which possess 3D score values distributed in the highest 0.5% region with reference to structures from DrugBank database. Mechanistic studies elucidated the origin of the observed regio- and stereoselectivities, which arise from distortion-controlled C-N coupling scenarios. This study expands the synthetic repertoire of energy transfer catalysis for accessing structurally intriguing architectures with high molecular complexity and underexplored topological chemical space.
... Although it is outside the scope of this account, we have also developed energy transfer-mediated, inter-, and intramolecular, dearomatizing, and nondearomatizing [2+2] cycloaddition reactions. [48][49][50][51] ...
Transition-metal cata-lyzed cross-coupling reactions are fundamental reactions in organic chemistry, facilitating strategic bond formations for accessing natural products, organic mate-rials, agrochemicals, and pharmaceuticals. Redox chemistry enables access to elusive cross-coupling mechanisms through single-electron processes as an alternative to classical two-electron strategies, which are predominated by palladium catalysis. The hallmark of this redox platform is the systematic modulation of transition-metal oxidation states by a photoredox catalyst or at a heterogeneous electrode sur-face. Electrocatalysis and photocatalysis enhance transition metal catalysis’ capacity for bond formation through electron- or energy-transfer processes. Cross-coupling conditions promoted by electrocatalysis and photocatalysis are mild and bond formation proceeds with exceptionally high chemoselectivity and wide functional group tolerance. The interfacing of abundant first-row transition-metal catalysis with electrocatalysis and photocatalysis has brought about a paradigm shift in cross-coupling technology. In particular, the merger of Ni catalysis with electro- and photochemistry ushered in a new era for carbon-carbon and carbon-heteroatom cross-couplings. We have developed enabling photo- and electrochemical methods throughout our research experience in industry (BMS, AstraZeneca), academia (Professor Baran, Scripps Research), and cross-disciplinary collaborative environments. In this Account, we will outline recent progress from our past and present labs in photo- and electrochemically mediated Ni-catalyzed cross-couplings. By highlighting these cross-coupling methodologies, we will also compare mechanistic features of both electro– and photochemical strategies for forging C(sp2)–C(sp3), C(sp3)–C(sp3), C–O, C–N, and C–S bonds. In each case study where we did not specifically develop both approaches, we will highlight related work from others for education. Through these side-by-side comparisons, we hope to demystify the subtle differences between the two complementary tools to enact redox control over transition metal catalysis. Finally, building off the collective experience of ourselves and the rest of the community, we propose a user guide to photo- and electrochemically-driven cross-coupling reactions to aid the practitioner in rapidly applying such tools in their synthetic designs.
... Recently, researchers have focused on identifying new chemical entities that can form specific diradicals mediated by the triplet-triplet energy transfer (TTEnT) from certain photosensitizers (Fig. 1b). For example, You, Oderinde and others employed a triplet-excited state of indoline derivatives for their [n+2] cycloaddition with alkenes [28][29][30][31][32] . Glorius and coworkers disclosed various diradical activation modes of quinoline species for their dearomative [n+2] cycloaddition with alkenes [33][34][35][36] . ...
Photocycloaddition is a powerful reaction to enable the conversion of alkenes into high-value synthetic materials that are normally difficult to obtain under thermal conditions. Lactams and pyridines, both prominent in pharmaceutical applications, currently lack effective synthetic strategies to combine them within a single molecular structure. Here we describe an efficient approach to diastereoselective pyridyl lactamization via a photoinduced [3+2] cycloaddition, based on the unique triplet-state reactivity of N–N pyridinium ylides in the presence of a photosensitizer. The corresponding triplet diradical intermediates allow the stepwise radical [3+2] cycloaddition with a broad range of activated and unactivated alkenes under mild conditions. This method exhibits excellent efficiency, diastereoselectivity and functional group tolerance, providing a useful synthon for ortho-pyridyl γ- and δ-lactam scaffolds with syn-configuration in a single step. Combined experimental and computational studies reveal that the energy transfer process leads to a triplet-state diradical of N–N pyridinium ylides, which promotes the stepwise cycloaddition.
... There are few examples of the synthesis of silicon-containing heterocycles. [11,12] Although researchers have shown the potential of the cycloaddition reactions of allene compounds for synthesizing nitrogen-and oxygen-containing heterocycles, [13,14] no examples of intramolecular [2 + 2] cycloaddition reactions between allenes and vinylsilanes have been reported in the literature. ...
This paper provides the first report of the intramolecular [2+2] cycloaddition of vinylsilane. The [2+2] cycloaddition of allenes is a useful reaction that can synthesize cyclobutanes. However, no previous works have attempted to control the regioselectivity between the two double bonds of allenes only by changing the reaction conditions, although there have been some reports of the regioselective [2+2] cycloaddition of allenes by changing the substrate. In this study, we have succeeded in controlling intramolecular [2+2] cycloaddition reactions at the proximal and distal positions of allenes simply by changing the reaction conditions. We found that the atomic radius of silicon is very important for perfect control of the reaction's sites. The structures of all key compounds were determined by the crystal sponge method which could identify the structures of liquid compounds.
... They are well suited for fragmentation or ring-enlargement reactions facilitated by their high ring strain [5][6][7][8][9][10]. While earlier examples were mainly focused on direct excitation of the substrates with highly energetic UV light [11][12][13][14], recent advances derived milder approaches by irradiation with visible light [15][16][17][18]. Over the last two decades, tremendous improvements on the field of enantioselective [2 + 2]-photocycloaddition reactions emerged from the pioneering work of the research groups of Bach [19,20], Meggers [21], Yoon [22,23] and others. ...
The intermolecular [2 + 2]-photocycloaddition of the parent flavone molecule (4) as the triplet energy-accepting species and the electron-rich alkene 2, 3-dihydrofuran (5) was performed by visible-light-mediated triplet-sensitization with an iridium-based organometallic sensitizer. The reaction proceeds with high diastereo- and regioselectivity (>98:2 for the regiochemical orientation and with 95% d.s.). In contrast to numerous other ene/enone combinations that are described in the literature and were also performed by us, the reaction between 4 and 5 almost solely afforded the cis-syn-cis cyclobutane 6, whereas analogous conjugated six- and five-membered cycloalkenones preferentially react to cis-anti-cis cyclobutanes or a mixture of both diastereoisomers (e.g., for the cyclohexanone-derived example 9).
Herein, a novel and facile organic photosensitizer (thioxanthone) mediated energy-transfer-enabled (EnT-enabled) dearomative [2+2] cycloaddition of aromatic heterocycle/maleimides for green synthesis of cyclobutane-fused polycyclic skeletons is reported. Mechanistic investigations revealed that...
A photocatalysed dearomative β-hydroborylation reaction of indole derivatives with NHC-boranes has been accomplished. This protocol shows a broad substrate scope with moderate to excellent yields, providing a novel and efficient...
Dearomative cycloaddition is a powerful technique to access sp3-rich three-dimensional structural motifs from simple flat, aromatic feedstock. The building-up of unprecedentedly diverse polycyclic scaffolds with increased saturation, and stereochemical information...
We report the synthesis of seven‐membered carbocycles through the dearomative intermolecular reaction of benzofurans with vinylcyclopropanes. The significant feature of this method involves activating benzofurans through energy transfer from an activated photocatalyst. Substituent effects were investigated for each substrate, and hydrocyclohepta[b]benzofurans with a tetrasubstituted carbon were obtained as a single diastereomer. This synthetic approach compliments the reported methodologies for synthesizing this type of skeleton and introduces a new feedstock for this skeleton with a different substitution pattern. Computational studies of the reaction mechanism suggested that the reaction proceeds stepwise through addition, small ring opening, and re‐cyclization. This novel synthetic approach opens up new possibilities for efficiently constructing seven‐membered carbocycles. Moreover, it provides a valuable platform for discovering unique molecules with diverse substitution patterns.
Dearomative photocycloadditions are valuable chemical transformations, serving as an efficient platform to create three-dimensional molecular complexity. However, the photolability of the original addition product especially within the context of ortho cycloadditions often causes undesired consecutive rearrangements, rendering these ortho cycloadducts elusive. Herein, we report an ortho-selective intermolecular photocycloaddition of bicyclic aza-arenes including (iso)quinolines, quinazolines, and quinoxalines by utilizing a strain-release approach. With bicyclo[1.1.0]butanes as coupling partners, this dearomative [2π + 2σ] cycloaddition enables the straightforward construction of C(sp3)-rich bicyclo[2.1.1]hexanes directly connected to N-heteroarenes. Photophysical experiments and DFT calculations revealed the origin of the [2π + 2σ] selectivity and indicate that, in addition to the originally proposed energy transfer or direct excitation pathways, a chain reaction mechanism is operative depending on the reaction conditions.
DNA-encoded library (DEL) screens have significantly impacted new lead compound identification efforts within drug discovery. An advantage of DELs compared to traditional screening methods is that an exponentially broader chemical space can be effectively screened using only nmol quantities of billions of DNA-tagged, drug-like molecules. The synthesis of DELs containing diverse, sp3-rich spirocycles, an important class of molecules in drug discovery, has not been previously reported. Herein, we demonstrate the synthesis of complex and novel spirocyclic cores via an on-DNA, visible light-mediated intermolecular [2 + 2] cycloaddition of olefins with heterocycles, including indoles, azaindoles, benzofurans, and coumarins. The DNA-tagged exo-methylenecyclobutane substrates were prepared from easily accessible alkyl iodides and styrene derivatives. Broad reactivity with many other DNA-conjugated alkene substrates was observed, including unactivated and activated alkenes, and the process is tolerant of various heterocycles. The cycloaddition was successfully scaled from 10 to 100 nmol without diminished yield, indicative of this reaction's suitability for DNA-encoded library production. Evaluation of DNA compatibility with the developed reaction in a mock-library format showed that the DNA barcode was maintained with high fidelity, with <1% mutated sequences and >99% amplifiable DNA from quantitative polymerase chain reaction (PCR) and next generation sequencing (NGS).
When mono‐radical ipso‐cyclization of aryl sulfonamides tend to undergo Smiles‐type rearrangement through aromatization‐driven C−S bond cleavage, diradical‐mediated cyclization must perform in a distinct reaction pathway. It is interesting meanwhile challenging to tune the rate of C−S bond cleavage to achieve a chemically divergent reaction of (hetero) aryl sulfonamides in a visible‐light induced energy transfer (EnT) reaction pathway involving diradical species. Herein a chemically divergent reaction based on the designed indole‐tethered (hetero)arylsulfonamides is reported which involves a diradical‐mediated ipso‐cyclization and a controllable cleavage of an inherent C−S bond. The combined experimental and computational results have revealed that the cleavage of the C−S bond in these substrates can be controlled by tuning the heteroaryl moieties: a) If the (hetero)aryl is thienyl, furyl, phenanthryl, etc., the radical coupling of double dearomative diradicals (DDDR) precedes over C−S bond cleavage to afford cyclobutene fused indolines by double dearomative [2+2]‐cycloaddition; b) if the (hetero)aryl is phenyl, naphthyl, pyridyl, indolyl etc., the cleavage of C−S bond in DDDR is favored over radical coupling to afford biaryl products.
An approach for 2‐acyl indolines synthesis through Cobalt‐catalyzed C−H activation/[3+2] annulation of aniline derivatives and acrylates is described. The method employs cobalt catalyst to afford a wide variety of functionalized 2‐acylindolines with high regioselectivity. The mechanism is investigated by KIE experiments and deuterium‐labeling experiment. The gram‐scale synthesis and synthetic transformations are also conducted, confirming the scalability and application value.
The rapid buildup of molecular complexity from simple precursors is a key goal in organic chemistry. One strategy to achieve this is through a dearomative cycloaddition wherein a 2D arene and alkene is converted to a 3D structure. In many cases this type of reactivity has been achieved with photochemistry. Despite the prospect of such a reaction, most known variants are intramolecular, which greatly limits the scope of chemical space that can be accessed. Intermolecular variants are known but are generally limited to heterocyclic systems such as indoles or quinolines. Herein, a method for intermolecular dearomative cycloaddition of simple naphthalenes with alkenes is presented. The reactions operate by a photoinduced sensitization of the arene. The bridged bicyclic products are generated with control of regiochemistry and function for a range of alkenes. In addition, the products can serve as useful intermediates as demonstrated in the synthesis of a biologically active benzazapine analog. Mechanistic studies are also included, which support reaction via a triplet excited state and that the selectivity can be rationalized by spin-density calculations.
Photochemical dearomative cycloaddition has emerged as a useful strategy to rapidly generate molecular complexity. Within this context, stereo- and regiocontrolled intermolecular para-cycloadditions are rare. Herein, a method to achieve photochemical cycloaddition of quinolines and alkenes is shown. Emphasis is placed on generating sterically congested products and reaction of highly substituted alkenes and allenes. In addition, the mechanistic details of the process are studied, which revealed a reversible radical addition and a selectivity-determining radical recombination. The regio- and stereochemical outcome of the reaction is also rationalized.
Irradiation of 1‐(penta‐3,4‐dienoyl)indole derivatives in the presence of an aromatic ketone by a high‐pressure mercury lamp through Pyrex glass gave two types of cyclized products stereoselectively in high combined yields. The major product was a tetracyclic indoline derivative containing anti‐Bredt‐type azabicyclo[4.2.0]octene moiety produced via photo [2+2] cycloaddition between indole and a distal double bond of allene, accompanied by a small amount of proximal [2+2] adduct. Among a range of aromatic ketones screened, 3',4'‐methylenedioxyacetophenone was found to sensitize the substrate most effectively. This article is protected by copyright. All rights reserved.
Cycloaddition reactions─epitomized by the Diels-Alder reaction─offer an arguably unmatched springboard for achieving chemical complexity, often with excellent selectivity, in a modular single step. We report the synthesis of aza-acenaphthenes in a single step by an unprecedented formal peri-(3 + 2) cycloaddition of simple quinolines with alkynes. A commercially available iridium complex exerts a dual role of photosensitizer and photoredox catalyst, fostering a cyclization/rearomatization cascade. The initial energy-transfer phase leads to the acenaphthene skeleton, while the ensuing redox shuttling step leads to aromatization. We applied this technology to 8-substituted quinolines and phenanthrolines, which smoothly reacted with both terminal and internal alkynes with excellent levels of regio- and diastereoselectivity. Density functional theory calculations revealed the intertwined EnT/SET nature of the process and offered guiding design principles for the synthesis of new aza-acenaphthenes.
The hydroarylation of alkynes, alkenes, and allenes is a cost-effective and efficient way to incorporate unsaturated moieties into aromatic substrates. This review focuses on gold-catalyzed hydroarylation, which produces aromatic alkenes, diaryl-alkanes, heterocycles, carbocycles, and arylbutadienes by directly functionalizing C-H bonds. Without the need for prefunctionalization, direct functionalization of aromatic C-H bonds with unsaturated moieties (alkyne, alkene, allene) provides an efficient synthetic strategy with fewer reaction steps. This review offers an overview of the recently developed hydroarylation processes catalyzed by gold. Mechanisms of hydroarylation via alkyne, alkene, allene, and arene activation receive special attention.
ConspectusExploring the enormous chemical space through an expedient building-up of molecular diversity is an important goal of organic chemistry. The development of synthetic methods toward molecules with unprecedented structural motifs lays the foundation for wide applications ranging from pharmaceutical chemistry to materials science. In this regard, the dearomatization of arenes has been recognized as a unique strategy since it provides novel retrosynthetic disconnections for various spiro or fused polycyclic molecules with increased saturation and stereoisomerism. However, inherent thermodynamic challenges are associated with dearomatization processes. The disruption of the aromaticity of arene substrates usually requires large energy inputs, which makes harsh conditions necessary for many ground-state dearomatization reactions. Therefore, further expansion of the scope of dearomatization reactions remains a major problem not fully solved in organic chemistry.The past decade has witnessed tremendous progress on photocatalytic reactions under visible light. Particularly, reactions via an energy transfer mechanism have unlocked new opportunities for dearomatization reactions. Mediated by appropriately chosen photosensitizers, aromatic substrates can be excited. This kind of precise energy input might make feasible some dearomatization reactions that are otherwise unfavorable under thermal conditions because of the significant energy increases of the substrates. Nevertheless, the lifetimes of key intermediates in energy-transfer-enabled reactions, such as excited-state aromatics and downstream biradical species, are quite short. How to regulate the reactivities of these transient intermediates to achieve exclusive selectivity toward a certain reaction pathway among many possibilities is a crucial issue to be addressed.Since 2019, our group has reported a series of visible-light-induced dearomative cycloaddition reactions for indole and pyrrole derivatives. It was found that the aromatic units in substrates can be excited under the irradiation of visible light in the presence of a suitable photosensitizer. These excited aromatics readily undergo various [m + n] cycloaddition reactions with appropriately tethered unsaturated functionalities including alkenes, alkynes, N-alkoxy oximes, (hetero)arenes, and vinylcyclopropanes. The reactions yield polycyclic indolines and pyrrolines with highly strained small- and/or medium-sized rings embedded, some of which possess unique bridge- or cagelike topologies. Systematic mechanistic studies confirmed the involvement of an energy transfer process. Density functional theory (DFT) calculations revealed the correlation between the substrate structure and the excitation efficiency, which accelerated the optimization of the reaction parameters. Meanwhile, DFT calculations demonstrated the competition between kinetically and thermodynamically controlled pathways for the open-shell singlet biradical intermediates, which allowed the complete switches from [2 + 2] cycloaddition to 1,5-hydrogen atom transfer in reactions with N-alkoxy oximes and to [4 + 2] cycloaddition in reactions with naphthalene. Furthermore, ab initio molecular dynamics (AIMD) simulations uncovered post-spin crossing dynamic effects, which determine the regioselectivity for the open-shell singlet biradical recombination step in the reactions of pyrrole-derived vinylcyclopropanes.An increasing number of scientists have joined in the research on visible-light-induced dearomative cycloaddition reactions and contributed to more elegant examples in this area. The visible-light-induced dearomatization reaction via energy transfer mechanism, although still in its infancy, has exhibited great potential in the synthesis of molecules that can hardly be accessed by other methods. We believe that future development will further push the boundary of organic chemistry and find applications in the synthesis of functional molecules and related disciplines.
A new strategy for the synthesis of highly versatile cyclobutylboronates via the photosensitized [2+2]‐cycloaddition of alkenylboronates and alkenes is presented. The process is mechanistically different from other processes in that energy transfer occurs with the alkenylboronate as opposed to the other alkene. This strategy allows for the synthesis of an array of diverse cyclobutylboronates. The conversion of these adducts to other compounds as well as their utility in the synthesis of melicodenine C is demonstrated. A process for the synthesis of cyclobutylboronates by [2+2]‐cycloaddition is presented. The reaction is enabled by triplet energy transfer to an alkenylboronate, which is an underexplored photochemical process. The process operates with a wide array of alkenylboronates and alkenes to generate a diverse range of products. The utility of the products is demonstrated in the synthesis of melicodenine C.
A new strategy for the synthesis of highly versatile cyclobutylboronates via the photosensitized [2+2]‐cycloaddition of alkenylboronates and alkenes is presented. The process is mechanistically different from other processes in that energy transfer occurs with the alkenylboronate as opposed to the other alkene. This strategy allows for the synthesis of an array of diverse cyclobutylboronates. The conversion of these adducts to other compounds as well as their utility in the synthesis of melicodenine C is demonstrated.
The photochemical synthesis of yet unknown 2‐oxospiro[azetidine‐3,3'‐indolines] (17 examples, 80‐95% yield), 2,4‐dioxospiro[azetidine‐3,3'‐indolines] (eight examples, 87‐97% yield), and 1‐oxo‐1,3‐dihydrospiro[indene‐2,3'‐indolines] (17 examples, 85‐97% yield) is described. Starting from readily accessible 3‐substituted indoles, a dearomatization of the indole core was accomplished upon irradiation at λ = 420 nm in the presence of thioxanthen‐9‐one (10 mol%) as the sensitizer. Based on mechanistic evidence (triplet energy determination, deuteration experiments, by‐product analysis) it is proposed that the reaction proceeds by energy transfer via a 1,4‐ or 1,5‐diradical intermediate. The latter intermediates are formed by excited state hydrogen atom transfer from suitable alkyl groups within the C3 substituent to the indole C2 carbon atom. Subsequent ring closure proceeds with pronounced diastereoselectivity to generate a 4‐ or 5‐membered spirocyclic dearomatized product with several options for further functionalization.
The photochemical synthesis of yet unknown 2‐oxospiro[azetidine‐3,3′‐indolines] (17 examples, 80–95 % yield), 2,4‐dioxospiro[azetidine‐3,3′‐indolines] (eight examples, 87–97 % yield), and 1‐oxo‐1,3‐dihydrospiro[indene‐2,3′‐indolines] (17 examples, 85–97 % yield) is described. Starting from readily accessible 3‐substituted indoles, a dearomatization of the indole core was accomplished upon irradiation at λ=420 nm in the presence of thioxanthen‐9‐one (10 mol%) as the sensitizer. Based on mechanistic evidence (triplet energy determination, deuteration experiments, by‐product analysis) it is proposed that the reaction proceeds by energy transfer via a 1,4‐ or 1,5‐diradical intermediate. The latter intermediates are formed by excited state hydrogen atom transfer from suitable alkyl groups within the C3 substituent to the indole C2 carbon atom. Subsequent ring closure proceeds with pronounced diastereoselectivity to generate a 4‐ or 5‐membered spirocyclic dearomatized product with several options for further functionalization.
Dearomatization reactions provide rapid access to structurally complex three-dimensional molecules from simple aromatic compounds. Plenty of reports have demonstrated their utilities in the synthesis of natural products, medicinal chemistry, and materials science in the last decades. Recently, visible-light mediated photocatalysis has emerged as a powerful tool to promote many kinds of transformations. The dearomatization reactions induced by visible-light have also made significant progress during the past several years. This review provides an overview of visible-light induced dearomatization reactions classified based on the manner in which aromaticity is disrupted.
Site-selective N -1 and C-3 arylation of indole has been sought after to achieve because of the prevalent application of arylindoles and the intricate reactivities led by multiple sites of N -unsubstituted indole. Represented herein is the first regioselective heteroarylation of indole via radical-radical cross-coupling by visible light irradiation. Steady and time-resolved spectroscopic and computational studies revealed that the hydrogen bonding interaction of organic base and its conjugated acid, respective with indole and heteroarylnitrile, determined the reaction pathway, which underwent either proton-coupled electron-transfer or energy-transfer for the subsequent radical-radical cross-coupling, leading to the regioselective formation of C-3 and N -1 heteroarylation of indoles, respectively. The parallel methodologies for regioisomeric N -1 and C-3 heteroaryl indoles with good functional group compatibility could be applied to gram-scale synthesis and late-stage derivatization of bioactive compounds under extremely mild reaction conditions.
Site‐selective N‐1 and C‐3 arylation of indole has been sought after because of the prevalent application of arylindoles and the intricate reactivities associated with the multiple sites of the N‐unsubstituted indole. Represented herein is the first regioselective heteroarylation of indole via a radical–radical cross‐coupling by visible‐light irradiation. Steady and time‐resolved spectroscopic and computational studies revealed that the hydrogen‐bonding interaction of organic base and its conjugated acid, namely with indole and heteroarylnitrile, determined the reaction pathway, which underwent either proton‐coupled electron‐transfer or energy‐transfer for the subsequent radical–radical cross‐coupling, leading to the regioselective formation of C‐3 and N‐1 heteroarylation of indoles, respectively. The parallel methodologies for regioisomeric N‐1 and C‐3 heteroaryl indoles with good functional group compatibility could be applied to large‐scale synthesis and late‐stage derivatization of bioactive compounds under extremely mild reaction conditions.
Radical recombination is among the fastest reactions in organic chemistry. Achieving high levels of selectivity in this type of reaction is rather challenging. In a recent report on visible-light-induced dearomative cycloaddition of pyrrole-tethered vinylcyclopropanes, extraordinary regioselectivity was observed during the intramolecular open-shell singlet biradical recombination step. In order to address the origin of this unusual selectivity, comprehensive computational studies have been performed, which suggests that it is not the result of any thermodynamic or kinetic factors but dominated by novel dynamic effects that are operational after the spin crossing from triplet to open-shell singlet state due to the unique shape of multi-spin-state potential energy surfaces. The results presented in this study provide new insights into how the dynamic effects can work in a multi-spin-state radical process and advance the understanding of a fundamental organic reaction.
Reaction of thiazoline fused 2-pyridones with alkyl halides in the presence of cesium carbonate opens the thiazoline ring via S-alkylation and generates N-alkenyl functionalized 2-pyridones. In the reaction with propargyl bromide, the thiazoline ring opens and subsequently closes via a [2 + 2] cycloaddition between an in situ generated allene and the α,β-unsaturated methyl ester. This method enabled the synthesis of a variety of cyclobutane fused thiazolino-2-pyridones, of which a few analogues inhibit amyloid β1–40 fibril formation. Furthermore, other analogues were able to bind mature α-synuclein and amyloid β1−40 fibrils. Several thiazoline fused 2-pyridones with biological activity tolerate this transformation, which in addition provides an exocyclic alkene as a potential handle for tuning bioactivity.
The photo-induced cleavage of C(sp2)-Cl bonds is an appealing synthetic tool in organic synthesis, but usually requires the use of high UV light, photocatalysts and/or photosensitizers. Herein is described a direct photo-induced chloroarene activation with UVA/blue LEDs that can be used in the reductive Heck cyclization of indoles and without the use of a photocatalyst or photosensitizer. The indole compounds examined display room-temperature phosphorescence. The photochemical reaction tolerates a panel of functional groups including esters, alcohols, amides, cyano and alkenes (27 examples, 50-88% yields), and can be used to prepare polycyclic compounds and perform the functionalization of natural product analogues in moderate to good yields. Mechanistic experiments, including time-resolved absorption spectroscopy, are supportive of photo-induced electron transfer between the indole substrate and DIPEA, with the formation of radical intermediates in the photo-induced dearomatization reaction.
Current medicinal chemistry relies heavily on the quality of building blocks, i. e. reagents used to introduce chemical diversity into the target molecules. The last decade witnessed an emergence of many novel (or well‐overlooked old) chemotypes for drug discovery, which is related to adapting new synthetic methodologies, designing new sp³‐enriched bioisosteres, paying attention to previously underrated (or even unwanted) structural motifs, or combination thereof. In this review with 532 references, a survey of selected chemotypes that emerged recently in medicinal chemistry is provided, with a focus on the synthesis of the corresponding building blocks. Thus, saturated (hetero)aliphatic boronates, sulfonyl fluorides, sulfinates, non‐classical sp³‐enriched benzene isosteres, bicyclic morpholine/piperidine/piperazine analogs, as well as gem‐difluorinated cycloalkanes (as an example of emerging fluorinated motifs) are discussed.
When aiming to synthesize molecules with elevated molecular complexity starting from relatively simple starting materials, photochemical transformations represent an open avenue to circumvent analogous multistep procedures. Specifically, light‐mediated cycloadditions remain as powerful tools to generate new bonds begotten from non‐very intuitive disconnections, that alternative thermal protocols would not offer. In response to the current trend in both industrial and academic research pointing towards green and sustainable processes, several strategies that meet these requirements are currently available in the literature. This Minireview summarizes [2+2] and [4+2] photocycloadditions that do not require the use of metal photocatalysts by means of alternative strategies. It is segmented according to the cycloaddition type in order to give the reader a friendly approach and we primarily focus on the most recent developments in the field carried out using visible light, a general overview of the mechanism in each case is offered as well.
A photoinduced pericyclic cascade reaction has been developed to afford oxabicyclo[4.2.0]octenes. Mechanistic studies show that this reaction undergoes [2 + 2]-photocycloaddition, base-promoted elimination, retro-4π-electrocyclization, [1,5]-H shift, and 4π-electrocyclization procedures. This reaction features wide substrate scope, good functional group tolerance, and excellent diastereoselectivity.
A concise approach for the synthesis of structurally diverse indoles enabled by RhIII-catalyzed switchable C2 C-H olefination and alkylation of N-quinolinyl indoles with alkenes as well as highly efficient C-H...
The dearomatizing photocycloaddition reaction is a powerful and effective strategy for synthesizing complex, three-dimensional, polycyclic scaffolds from simple aromatic precursors. Generally, the dearomatizing photocycloaddition reaction is promoted by visible light and occurs via an energy transfer (EnT) process. This mini-review provides an overview of recent advances in this area (2018-2020), encompassing both intramolecular and intermolecular transformations. While the majority of the studies are centered on intramolecular processes due to their predictable regio- and stereo-selectivity, intermolecular transformations that show an exceptionally broad substrate scope are beginning to emerge.
A visible‐light‐induced photoredox [2+2]‐cycloaddition/retro‐Mannich‐type reaction was developed for the concise synthesis of cyclohepta[b]indoles, which is initiated by a novel process of single‐electron transfer from the enaminone moiety.
Abstract
A novel method for the concise synthesis of cyclohepta[b]indoles in high yields was developed. The method involves a visible‐light‐induced, photocatalyzed [2+2]‐cycloaddition/ retro‐Mannich‐type reaction of enaminones. Experimental and computational studies suggested that the reaction is a photoredox process initiated by single‐electron oxidation of an enaminone moiety, which undergoes subsequent cyclobutane formation and rapidly fragmentation in a radical‐cation state to form cyclohepta[b]indoles.
A novel method for the concise synthesis of cyclohepta[b]indoles in high yields was developed. The method involves a visible‐light‐induced, photocatalyzed [2+2]‐cycloaddition/ retro‐Mannich‐type reaction of enaminones. Experimental and computational studies suggested that the reaction is a photoredox process initiated by single‐electron oxidation of an enaminone moiety, which undergoes subsequent cyclobutane formation and rapidly fragmentation in a radical‐cation state to form cyclohepta[b]indoles.
This paper describes an intermolecular cross-selective [2 + 2] photocycloaddition reaction of exocyclic arylidene oxetanes, azetidines, and cyclobutanes with simple electron-deficient alkenes. The reaction takes place under mild conditions using a commercially available Ir(III) photosensitizer upon blue light irradiation. This transformation provides access to a range of polysubstituted 2-oxaspiro[3.3]heptane, 2-azaspiro[3.3]heptane, and spiro[3.3]heptane motifs, which are of prime interest in medicinal chemistry as gem-dimethyl and carbonyl bioisosteres. A variety of further transformations of the initial cycloadducts are demonstrated to highlight the versatility of the products and enable selective access to either of a syn- or an anti-diastereoisomer through kinetic or thermodynamic epimerization, respectively. Mechanistic experiments and DFT calculations suggest that this reaction proceeds through a sensitized energy transfer pathway.
Herein we report visible‐light‐induced intramolecular double dearomative cycloaddition of arenes. Compared with the well‐known photodimerization of arenes under ultraviolet irradiation, the current reactions are carried out under mild conditions and feature wide substrate scope. A large array of structurally‐diverse polycyclic indoline derivatives is afforded in high yields (up to 98 %) with exclusive diastereoselectivity (>20:1 dr) via dearomative [4+2] or [2+2] pathway.
The visible‐light‐induced intramolecular double dearomative cycloaddition of arenes is reported. The reactions are carried out under mild conditions and feature a wide substrate scope. A large array of polycyclic indoline derivatives is afforded via dearomative [4+2] or [2+2] cycloaddition pathways in high yields with exclusive diastereoselectivity.
Abstract
Herein we report visible‐light‐induced intramolecular double dearomative cycloaddition of arenes. Compared with the well‐known photodimerization of arenes under ultraviolet irradiation, the current reactions are carried out under mild conditions and feature wide substrate scope. A large array of structurally‐diverse polycyclic indoline derivatives is afforded in high yields (up to 98 %) with exclusive diastereoselectivity (>20:1 dr) via dearomative [4+2] or [2+2] pathway.
The [2+2] photocycloaddition reaction between an imine and an alkene component, the aza Paternò-Büchi reaction, is one of the most efficient ways to synthesize functionalized azetidines. However, the application of the aza Paternò-Büchi reaction has been met with limited success due to the inherent challenges associated with this approach. This review covers the current scope and limitations of reported examples of aza Paternò-Büchi reactions in organic synthesis. An outlook is provided, which highlights recent improvements and the discovery of new reaction protocols that have overcome some long-standing challenges within this field of research.
A variety of highly functionalised N-containing polycycles (35 examples) are synthetised from simple indoles and aromatic ketones through a mild visible-light Paternò-Büchi process. Tetrahydrooxeto[2,3-b]indole scaffolds, with up to three contiguous all-substituted stereocenters, are generated in high yield (up to >98%) and excellent site- regio- and diastereocontrol (>20:1). The use of visible light (405 or 465 nm) ensures enhanced performances by switching off undesired photodimerisation side reactions. The reaction can be easily implemented under a microfluidic photoreactor with improved productivity (up to up to 0.176 mmol·h-1) and generality. Mechanistic investigations revealed that two alternative reaction mechanisms can account for the excellent regio- and diasterecontrol observed.
Multicomponent reactions have become a mainstay in both academic and industrial synthetic organic chemistry owing to their step- and atom-economy advantages over traditional synthetic sequences1. Recently, bicyclo[1.1.1]pentane (BCP) motifs have come to the fore as valuable pharmaceutical bioisosteres of benzene rings, and, in particular, 1,3-disubstituted BCP moieties have become widely adopted in medicinal chemistry as para-phenyl ring replacements2. Often these structures are generated from [1.1.1]propellane via opening of the internal C–C bond, through the addition of either radicals or metal-based nucleophiles3–13. The resulting propellane-addition adducts are subsequently transformed to the requisite polysubstituted BCP compounds via a range of synthetic sequences that traditionally involve multiple chemical steps. While this approach has been effective so far, it is clear that a multicomponent reaction that enables single-step access to complex and diverse polysubstituted BCP products would be synthetically advantageous over the current stepwise approaches. Here we report a one-step three-component radical coupling of [1.1.1]propellane to afford diverse functionalized bicycles using various radical precursors and heteroatom nucleophiles via a metallaphotoredox catalysis protocol. The reaction operates on short timescales (five minutes to one hour) across multiple (>10) nucleophile classes and can accommodate a diverse array of radical precursors, including those which generate alkyl, α-acyl, trifluoromethyl, and sulfonyl radicals. This method has been used to rapidly prepare BCP analogues of known pharmaceuticals, one of which has pharmacokinetic properties substantially different to those of its commercial progenitor.
Lanthanide photocatalysts are much less investigated in synthetic chemistry than rare and expensive late transition metals. We herein introduce GdIII photocatalysis of a highly regioselective, intermolecular [2+2] photocycloaddition/ring‐expansion sequence with indoles, which could provide divergent access to cyclopenta[b]indoles and indolines. A simple and commercially available Gd(OTf)3 salt is sufficient for this visible‐violet‐light‐induced transformation. The reaction proceeds either through a transient or start‐to‐end dearomatization cascade and shows excellent regioselectivity (usually >95:5 r.r.), broad scope (59 examples), good functional group tolerance and facile scale‐up under mild, direct visible‐light‐excitation conditions. Mechanistic investigations reveal that direct excitation of the Gd(OTf)3/indole mixture gives an excited state intermediate, which undergoes the subsequent [2+2] cycloaddition and cyclobutane‐expansion cascade.
The visible light‐promoted intramolecular [2+2] cycloaddition of N‐allylcinnamamines and N‐allylcinnamamides in the presence of catalytic amounts of [Ir{dF(CF3)ppy}2(dtbpy)]PF6 is reported. Low energy visible light and a high triplet energy iridium‐photosensitizer were efficient at promoting the cycloaddition reaction of N‐allylcinnamamides and N‐allylcinnamamines to the corresponding aryl‐3‐azabicyclo[3.2.0]heptanones and aryl‐3‐azabicyclo[3.2.0]heptanes, respectively, with high diastereoselectivity and under mild conditions. Azabicyclic fused rings have been employed as surrogates for piperidine motifs in drug discovery. Functional groups useful for deployment and/or elaboration in drug discovery campaigns were all shown to be tolerated, including halides, CF3, cyanide, ester, acetamide, acetate, CH3O, pyridyl, furan, carbamate, tosyl, benzyl, and benzoate.
Discovery of enantioselective catalytic reactions for the preparation of chiral compounds from readily available precursors, using scalable and environmentally benign chemistry, can greatly impact their design, synthesis and eventually manufacture on scale. Functionalized cyclobutanes and cyclobutenes are important structural motifs seen in many bioactive natural products and pharmaceutically relevant small molecules. They are also useful precursors for other classes of organic compounds such as other cycloalkane derivatives, heterocyclic compounds, stereo-defined 1,3-dienes and ligands for catalytic asymmetric synthesis. The simplest approach to make cyclobutenes is through an enantioselective [2+2]-cycloaddition between an alkyne and an alkenyl derivative, a reaction which has a long history. Yet known reactions of this class that give acceptable enantioselectivities are of very narrow scope and are strictly limited to activated alkynes and highly reactive alkenes. Here we disclose a broadly applicable enantioselective [2+2]-cycloaddition between wide variety of alkynes and alkenyl derivatives, two of the most abundant classes of organic precursors. The key cycloaddition reaction employs catalysts derived from readily synthesized ligands and an earth-abundant metal, cobalt. Over 50 different cyclobutenes with enantioselectivities in the range of 86-97% ee are documented. With the diverse functional groups present in these compounds, further diastereoselective transformations are easily envisaged for synthesis of highly functionalized cyclobutanes and cyclobutenes. Some of the novel observations made during these studies including a key role of a cationic Co(I)-intermediate, ligand and counter ion effects on the reactions, can be expected to have broad implications in homogeneous catalysis beyond the highly valuable synthetic intermediates that are accessible by this route.
The union of photoredox and nickel catalysis has resulted in a renaissance in radical chemistry as well as in the use of nickel‐catalyzed transformations, specifically for carbon–carbon bond formation. Collectively, these advances address the longstanding challenge of late‐stage cross‐coupling of functionalized alkyl fragments. Empowered by the notion that photocatalytically generated alkyl radicals readily undergo capture by Ni complexes, wholly new feedstocks for cross‐coupling have been realized. Herein, we highlight recent developments in several types of alkyl cross‐couplings that are accessible exclusively through this approach.
Visible‐light photocatalysis is a rapidly developing and powerful strategy to initiate organic transformations, as it closely adheres to the tenants of green and sustainable chemistry. Generally, most visible‐light‐induced photochemical reactions occur through single‐electron transfer (SET) pathways. Recently, visible‐light‐induced energy‐transfer (EnT) reactions have received considerable attentions from the synthetic community as this strategy provides a distinct reaction pathway, and remarkable achievements have been made in this field. In this Review, we highlight the most recent advances in visible‐light‐induced EnT reactions.
A visible-light-promoted iridium photoredox and nickel dual-catalyzed cross-coupling procedure for the formation C-N bonds has been developed. With this method, various aryl amines were chemoselectively cross-coupled with electronically and sterically diverse aryl iodides and bromides to forge the corresponding C-N bonds, which are of high interest to the pharmaceutical industries. Aryl iodides were found to be a more efficient electrophilic coupling partner. The coupling reactions were carried out at room temperature without the rigorous exclusion of molecular oxygen, thus making this newly developed Ir-photoredox/Ni dual-catalyzed procedure very mild and operationally simple.
The phenyl cation is known to have two low-energy minima, corresponding to 1
A
1 and 3
B
1 states, the first of which is more stable by ca. 25 kcal/mol. The minimum energy crossing point between these two surfaces,
located at various levels including a hybrid method first described here, lies just above the minimum of the triplet, 0.12
kcal/mol at the CCSD(T)/cc-pVDZ//B3LYP/SV level, and there is significant spin-orbit coupling between the surfaces at this
point. On the basis of these results, the lifetime of the triplet is expected to be very short.
One of the most efficient ways to synthesize oxetanes is the light-enabled [2 + 2] cycloaddition reaction of carbonyls and alkenes, referred to as the Paternò-Büchi reaction. The reaction conditions for this transformation typically require the use of high energy UV light to excite the carbonyl, limiting the applications, safety, and scalability. We herein report the development of a visible-light-mediated Paternò-Büchi reaction protocol that relies on triplet energy transfer from an iridium-based photocatalyst to the carbonyl substrates. This mode of activation is demonstrated for a variety of aryl glyoxylates and negates the need for both visible-light-absorbing carbonyl starting materials and UV light to enable access to a variety of functionalized oxetanes in up to 99% yield.
Visible-light promoted dearomative [2+2] cycloaddition of indole derivatives tethered with olefins at N1 position has been considered thermodynamically unfeasible due to the high triplet excited-state energies. We describe visible-light-promoted [2+2] cycloaddition with concomitant dearomatization of indole derivatives tethered with olefins at N1 position via energy transfer process, providing cyclobutane-fused polycyclic indoline derivatives which are potentially useful in drug design and discovery. These cyclobutane-fused indoline-based polycycles are obtained in high yields and with good diastereoselectivities (> 99:1). The key to the success of the reaction is the formation of H-bond(s) between N-alkenoylindole and solvent, ena-bling the reduction of the triplet energy of the indole derivatives, which greatly improved the efficiency of the protocol. The applicability of the method is demonstrated by late-stage skeletal diversification of indole-containing bioactive molecules, which provides a powerful strategy for the rapid skeleton remodeling. DFT calculations were used to give a deep under-standing of the reaction pathways.
The pressure to deliver new medicines to the patient continues to grow along with increases in compound failure rate; thus, putting the current R&D model at risk. Analysis has shown that increasing the three-dimensionality of po-tential drug candidates decreases the risk of failure and improves binding selectivity and frequency. For this reason many workers have taken a new look at the power of photochemistry, as a means to generate novel sp3 rich scaffolds for use in drug discovery programs. Here we report the design, synthesis and computational structural analysis of a series of 2,4-methanoprolines having inherent 3D character (PMI and PBF Scores) significantly higher than that of the broader AbbVie Rule of 3 (Ro3) collection.
Pinpointing proteins
To develop drugs that target a specific cell surface protein, it's helpful to know which other proteins reside in its vicinity. Geri et al. report a light-triggered labeling technique that improves the spatial resolution for this type of mapping. Specifically, they rely on a photocatalyst with a very short energy-transfer range to activate a carbene-based label that can only diffuse a short distance in water before reacting. They showcase the technique by mapping the environment of the programmed-death ligand 1 (PDL1) protein on B cell surfaces, a system of considerable interest in cancer immunotherapy.
Science , this issue p. 1091
In general, heterocyclic compounds are a significant source of pharmacologically active compounds. Among them, the indole scaffold widely distributes in natural products and bioactive molecules including anti-cancer agents. In view of its unique physic-chemical and biological properties, it has been used as a privileged scaffold in the anti-cancer agents design. So far, many natural and synthetic indole derivatives have been discovered as promising anti-cancer agents used in clinic or clinical evaluations, suggesting its prominent place in anti-cancer drugs development. This review aimed to provide a clear knowledge on the recent development of indoles as anti-cancer agents, such as myeloid cell leukemia-1 (Mcl-1) inhibitors, proviral insertion site in moloney murine leukemia virus (Pim) inhibitors, histone deacetylase (HDAC) inhibitors, silent mating type information regulation 2 homolog (SIRT) inhibitors and tubulin inhibitors, and made an insight into the corresponding structure-activity relationships (SARs). We hope the review could give a guide to develop new anti-cancer agents with greater potency against drug-sensitive and drug-resistant cancers in the future.
The use of visible light and photoredox catalysis emerged as a powerful and sustainable tool for organic synthesis, showing the high value of distinctly different ways of bond creation. Indoles and related heterocycles are widely-present in natural products, biologically active compounds, drugs, and agrochemicals. This review summarises the impact of visible light-promoted chemistry on the functionalization of indoles and on the synthesis and modification of indolines, indolin-2-ones, indolin-3-ones, and isatins. Almost 100 references starting from 2012 are cited.
The discovery of novel (catalytic) transformations and mechanisms is commonly based on rational design. However, many discoveries have resulted directly from experimental serendipity. Building on this, we report a two-dimensional screening protocol, combining “mechanism-based” and “reaction-based” screening and its application to the field of visible light photocatalysis. To this end, two energy-transfer-based cycloaddition reactions could be realized: a notably endergonic energy transfer process allows for the dearomative cycloaddition of benzothiophenes and related heterocycles. Moreover, by sensitization of enone moieties, a [2+2]-cycloaddition to alkynes and an unexpected cycloaddition-rearrangement cascade were discovered. Advanced spectroscopic techniques (in particular transient absorption spectroscopy and pulse radiolysis) were utilized to investigate the underlying photophysical processes and gain insight into reaction kinetics. Combining these results with further mechanistic analysis can eventually turn out to be helpful upon knowledge-driven development of improved systems. Such screening approaches can thus provide complementary access toward novel and more efficient catalytic protocols.
We report the highly enantioselective [2+2] cycloaddition of simple cinnamate esters, the products of which are useful synthons for the controlled assembly of cyclobutane natural products. This method utilizes a co-catalytic system in which a chiral Lewis acid accerates the transfer of triplet energy from an excited-state Ir(III) photocatalyst to the cinnamate ester. Computational evidence indicates that the principal role of the Lewis acid co-catalyst is to lower the absolute energies of the substrate frontier molecular orbitals, leading to greater electronic coupling between the sensitizer and substrate and increasing the rate of the energy transfer event. These results suggest Lewis acids can have multiple beneficial effects on triplet sensitization reactions, impacting both the thermodynamic driving force and kinetics of Dexter energy transfer.
An intramolecular dearomatization of indole derivatives based on visible-light-promoted [2 + 2] cycloaddition was achieved via energy transfer mechanism. The highly strained cyclobutane-fused angular tetracyclic spiroindolines, which were typically unattainable under thermal conditions, could be directly accessed in high yields (up to 99%) with excellent diastereoselectivity (>20:1 dr) under mild conditions. The method was also compatible with diverse functional groups and amenable to flexible transformations. In addition, DFT calculations provided guidance on the rational design of substrates and deep understanding of the reaction pathways. This process constituted a rare example of indole functionalization by exploiting visible-light-induced reactivity at the excited states.
This paper describes the development and mechanistic studies of a general, high-yielding amine Cα–H cyanation protocol via photoredox catalysis. Inexpensive NaCN is employed as the cyanide source and air is the external oxidant, resulting in mild and highly functional group tolerant conditions. Notably, efficient Cα–H cyanations of secondary and tertiary aliphatic amines and of complex, biologically active compounds (drugs) can be performed using the established methodology. Mechanistic studies suggest that the carboxylic acid additive has three effects: formation of a stabilizing hemiaminal intermediate, prevention of catalyst decomposition by protonating the substrate, and modulation of fluorescence quenching of the photoexcited catalyst species.
Harnessing visible light to access excited (triplet) states of organic compounds can enable impressive reactivity modes. This tutorial review covers the photophysical fundamentals and most significant advances in the field of visible-light-mediated energy transfer catalysis within the last decade. Methods to determine excited triplet state energies and to characterize the underlying Dexter energy transfer are discussed. Synthetic applications of this field, divided into four main categories (cyclization reactions, double bond isomerizations, bond dissociations and sensitization of metal complexes), are also examined.
The development and application of dearomative cascade photoca-talysis as a strategy in complex molecule synthesis is described. Visible light-absorbing photosensitizers were used to (sequentially) activate an arene precursor to divergently form two different poly-cyclic molecular scaffolds through catalyst selective energy transfer.
A novel method for the catalytic asymmetric dearomatization by visible‐light‐activated [2+2] photocycloaddition with benzofurans and one example of a benzothiophene is reported, providing chiral tricyclic structures with up to four stereocenters including quaternary stereocenters. The benzofurans and the benzothiophene are functionalized at the 2‐position with a chelating N‐acylpyrazole moiety which permits the coordination of a visible light activatable chiral‐at‐rhodium Lewis acid catalyst. Computational molecular modeling revealed the origin of the unusual regioselectivity and identified the heteroatom in the heterocycle to be key for the regiocontrol.
We have developed a rapid two-step synthesis of substituted 3 azabicyclo[3.2.0]heptanes which are attractive building blocks for drug discovery. This new method utilizes very common chemicals - benzaldehyde, allylamine and cinnamic acid, - via intramolectular [2+2] photochemical cyclization.
Indoles constitute extensively explored heterocyclic ring systems with wide range of applications in pathophysiological conditions that is, cancer, microbial and viral infections, inflammation, depression, migraine, emesis, hypertension, etc. Presence of indole nucleus in amino acid tryptophan makes it prominent in phytoconstituents such as perfumes, neurotransmitters, auxins (plant hormones), indole alkaloids etc. The interesting molecular architecture of indole makes them suitable candidates for the drug development. This review article provides an overview of the chemistry, biology, and toxicology of indoles focusing on their application as drugs. Our effort is to corroborate the information available on the natural indole alkaloids, indole based FDA approved drugs and clinical trial candidates having diverse therapeutic implementations. This compiled information may serve as a benchmark for the alteration of existing ligands to design novel potent molecules with lesser side effects.
Generally, heterocycles occupy a prominent place in chemistry due to their wide range of applications in the fields of drug design, photochemistry, agrochemicals, dyes and so on.Among them, indole scaffolds have been found in most of the important synthetic drug molecules and paved a faithful way to develop effective targets.Privileged structures bind to multiple receptors with high affinity, thus aiding the development of novel biologically active compounds.Among the indole class of compounds, 2-arylindoles appear to be a most promising lead for drug development.The derivatives of 2-arylindoles exhibits antibacterial, anticancer, anti-oxidants, anti-inflammatory, anti-diabetic, antiviral, antiproliferative, antituberculosis activity, etc.This article would provide a clear knowledge on the wide-ranging biological activities of 2-arylindoles over the past two decades, which would be beneficial for the designing of more potent drug targets in order to compete with the existing drugs.
The [2 + 2] photocycloaddition is undisputedly the most important and most frequently used photochemical reaction. In this review, it is attempted to cover all recent aspects of [2 + 2] photocycloaddition chemistry with an emphasis on synthetically relevant, regio-, and stereoselective reactions. The review aims to comprehensively discuss relevant work, which was done in the field in the last 20 years (i.e., from 1995 to 2015). Organization of the data follows a subdivision according to mechanism and substrate classes. Cu(I) and PET (photoinduced electron transfer) catalysis are treated separately in sections 2 and 4 , whereas the vast majority of photocycloaddition reactions which occur by direct excitation or sensitization are divided within section 3 into individual subsections according to the photochemically excited olefin.
Tumours of the central nervous system are intrinsically more dangerous than tumours at other sites, and in particular, brain tumours are responsible for 3% of cancer deaths in the UK. Despite this, research into new therapies only receives 1% of national cancer research spend. The most common chemotherapies are temozolomide, procarbazine, carmustine, lomustine and vincristine, but because of the rapid development of chemoresistance, these drugs alone simply aren't sufficient for long-term treatment. Such poor prognosis of brain tumour patients prompted us to research new treatments for malignant glioma, and in doing so, it became apparent that aromatic heterocycles play an important part, especially the indole, carbazole and indolocarbazole scaffolds. This review highlights compounds in development for the treatment of tumours of the central nervous system which are structurally based on the indole, carbazole and indolocarbazole scaffolds, under the expectation that it will highlight new avenues for research for the development of new compounds to treat these devastating neoplasms.
Copyright © 2014 Elsevier Masson SAS. All rights reserved.
The first examples of enantioselective intermolecular [2+2] photocycloadditions of isoquinolone with alkenes are reported. Photoreactions were carried out at low temperature in the presence of a chiral hydrogen-bonding template, which effectively shields one face of the substrate through formation of a hydrogen-bonded supramolecular complex. Functionalized cyclobutane products were obtained in excellent yields (86-98%) and with outstanding regio-, diastereo-, and enantioselectivity (88-99% ee).
A highly diastereoselective and regioselective [2+2]-cycloaddition reaction of 3-ylideneoxindoles has been accomplished using visible light photocatalysis. This visible light photocatalytic protocol allows an expedient access to diversely functionalized and structurally constrained oxindole derivatives containing two spirocycles and four stereogenic centers, including two all-carbon quaternary centers.
Irradiation of N-acylindoles in the presence of olefins produces cyclobutanes by cycloaddition of the olefin to the indole 2,3-double bond.
The regio- and stereo-selectivities in the [2 + 2] photocycloaddition of a series of 1-benzoylindoles with vinyl acetate and methyl acrylate have been investigated. With some exceptions, the 1 -benzoylindoles gave exclusively or predominantly the corresponding 1-acetoxy-3-benzoyl and 3-benzoyl-1-methoxycarbonyl-1,2,2a,7b-tetrahydro-3H-cyclobut[b]indoles as mixtures of stereoisomers.
The 1,4-biradical species previously proposed as intermediates in the formation of cyclobutane adducts in the photochemical cycloaddition reaction between N-benzoylindole and alkenes have been trapped with hydrogen selenide. The structures of the trapped biradicals are consistent with the proposal that the first bond formed between the triplet excited state of the indole derivative and the alkenes is from the indole 2-position to that terminus of the alkene which is less able to stabilise a radical centre. This allows prediction of the reaction regiochemistry.
Aus Phenylhydrazin (I) und Cycloalkanonen (II) entstehen über die Hydrazone (III) nach Fischer die 2,3-Polymethylen-indole (IV), die zu (Vc) und (Vd) methyliert werden.
The photochemical cycloaddition reaction of N-benzoylindole with 1,6-heptadiene, tetramethylethylene, and vinylcyclopropane has been examined. The structures of the products suggest that the reaction proceeds via a 1,4-biradical intermediate that is formed by bonding between one terminus of the alkene and the 2-position of the indole derivative. This result is used to explain the origin of the previously observed regioselectivity of the photochemical cycloaddition reaction. The biradical intermediates obtained in the photochemical cycloaddition reaction of N-benzoylindole with vinylcyclopropane and 1,6-heptadiene can undergo rearrangement reactions whose rate constants can be estimated. Using these rates as clocks, the lifetimes of the intermediate biradicals in the photochemical cycloaddition reaction of N-benzoylindole with alkenes are estimated to be of the order of 100 ns. The consequences of this for the potential success of synthetically useful trapping of the intermediate biradicals is discussed.
The chemistry of 1,3 and 1,4 diradical species derived from different sources is discussed in terms of their origins, and structures. Singlet diradicais produced from azo compounds and Norrish type II photoreactions behave differently from those produced via small ring pyrolyses. The properties of these and triplet diradicals are analyzed.
Direct photolysis of 1,2,3-trimethyl-5,6-dicyanonorbornadiene (4) at 366 nm induces valence isomerization to the corresponding quadricyclene compound, 5, with a quantum yield of 0.68 ± 0.01. The same transformation occurs in the presence of a number of triplet photosensitizers. Thus Ru(bpy)32+ (bpy is 2,2′-bipyridine), whose emissive metal-to-ligand charge-transfer excited state is quenched by 4 with a rate constant of 2.0 ± 0.2 × 108 M-1 s-1, sensitizes the production of 5 at 546 nm with a limiting quantum yield of 0.06 ± 0.01. Limiting yields at 436 nm for the organic sensitizers biacetyl and 9-fluorenone are 0.11 ± 0.01 and 0.15 ± 0.01, respectively. The finding that direct photoisomerization occurs with much higher efficiency than the triplet-sensitized process suggests that the lowest excited singlet state of 4 is significantly more reactive than the triplet state. Interestingly, the opposite reactivity pattern obtains in the case of the unsubstituted norbornadiene molecule. Possible reasons for this substituent effect are discussed in terms of the excited-state potential energy surfaces that interconnect the norbornadiene and quadricyclene structures.
Hip to be square: Styrenes participate in [2+2] cycloadditions upon irradiation with visible light in the presence of an iridium(III) polypyridyl complex. In contrast to previous reports of visible light photoredox catalysis, the mechanism of this process involves photosensitization by energy transfer and not electron transfer.
Abstract— Quenching of the triplet states of the aromatic ketones (KCO), benzophenone, acetophenone and xanthone, by indole and 3-methyl indole gives rise to the neutral radicals resulting from hydrogenatom transfer with variable efficiency (40–100%). Thus in addition to the reaction,
3KCO*+RH →KCOH +R.
some other quenching path or paths occur. There is no evidence for any triplet energy transfer even when this is energetically favourable, and it is suggested therefore that quenching to give ground state species following favourable charge-transfer interactions accounts for the proportion of quenching without reaction.
The spectra of the indole radicals, R., were determined and the kinetics of their decay in aerated and deaerated solution were investigated and reaction schemes proposed to explain these observations.
The [2 + 2] photocycloaddition reaction of 2(5H)-furanone to ethylene and acetylene has been investigated by means of DFT and CASSCF methods. In both cases, the reaction involves the formation of a triplet 1,4-biradical intermediate that evolves to the cyclobutane product after spin inversion. For acetylene, the lowest energy path in the triplet surface occurs through the (3)(pi-pi*) state of the 2(5H)-furanone. However, in the reaction with ethylene the lowest energy path in the triplet surface involves the (3)(pi-pi*) state of the alkene. Although reaction through the triplet state of olefins is usually disregarded due to the short lifetime of these species, we have experimentally measured that sensitization of ethylene triplet state can occur at typical synthetic conditions and, thus, lead to photochemical addition to the lactone.